One of the important targets for developing a causal therapy for Alzheimer's disease (AD) is represented by synapses. The nitric oxide signaling pathway is thought to play an important role in the synapse during plasticity and memory. Published data from Dr. Arancio's laboratory have demonstrated the involvement of the pathway in amyloid-beta-induced synaptic dysfunction. Most importantly, sildenafil, an inhibitor of the cGMP-degrading enzyme phosphodiesterase V (PDE5), one of the components of the pathway, ameliorates synaptic and memory abnormalities in an amyloid-depositing mouse model, the APP/PS1 animal. Thus, the overall purpose of this project is to identify molecules that, by enhancing cGMP levels, re-establish normal cognition in the APP/PS1 mouse model. None of the existing PDE5 inhibitors has been developed to counteract diseases of the CNS and at the same time possesses the selectivity required for chronic administration to an elderly population with comorbid conditions such as AD patients. To that end, a new compound has been synthesized in our laboratories that will serve for lead optimization. YF012403 has high potency and excellent selectivity for PDE5 over other PDE isoforms. Moreover, it crosses the blood brain barrier, and has not shown acute toxicity signs. Most importantly, it ameliorates beta-amyloid induced synaptic and memory dysfunction. The following aims will be addressed by combining med/chem expertise with expertise on the biology of AD and mouse models of the disease: a) to design and synthesize novel PDE5 inhibitors which are optimized for AD; b) to identify compounds with high affinity and good selectivity for PDE5; c) to determine whether new PDE5 inhibitors have good pharmacokinetic and are safe; d) to screen the new PDE5 inhibitors by selecting compounds that rescue synaptic dysfunction in APP/PS1 mice; e) to further screen PDE5 inhibitors selected through tests on synaptic function to examine if they prevent cognitive abnormalities in APP/PS1 mice. On the completion of these studies we will identify a new drug for the treatment of cognitive loss in AD. The whole project will be organized in clear milestones with objective success/failure criteria and GO/NO GO decision points. PUBLIC HEALTH RELEVANCE STATEMENT: Currently used therapies against Alzheimer's disease have limited efficacy. We have found that phosphodiesterase 5 inhibitors might counteract memory deficits in animal of the disease. However, none of the existing inhibitors has been developed to counteract CNS diseases. We now propose to find phosphodiesterase 5 inhibitors that might be used in chronic CNS diseases such as Alzheimer's disease.